The process of development and differentiation are influenced by chemomechanical forces generated by the structural network of the cell. The cell structural network includes the interconnected extracellular matrix, cell adhesion molecules, cytoskeleton, and nuclear matrix. Multiple studies support the role of these components in development and differentiation. Alterations in the structural components of the cell often accompany neoplastic progression although the significance of these changes to loss of growth controls in neoplastic cells is poorly understood. Recent findings from our laboratory implicate a tumor suppressor gene product in an intrinsic block of cellular growth responses to growth factor signals under conditions that are cell shape- or attachment-dependent. Cells that have lost a tumor suppressor gene (supB-) do not exhibit autonomous anchorage-independent growth but grow in soft agar in the presence of serum and growth factors. Cells that retain tumor suppressing ability (supb+) are growth inhibited in agar even in the presence of growth factors, although growth factor receptor numbers and affinities are the same for supB4 and supb- cells. Both cell types grow similarly on a plastic substrate in the presence and absence of additional growth factors, indicating that the block to growth factor mediated mitogenesis in supB+, cells is related to cell shape or attachment. The supB- cells exhibit alterations in the expression and organization of several components of the cell structural network, including the actin cytoskeleton, cell adhesion molecules, extracellular matrix molecules, and possibly the nuclear matrix. Our working hypothesis is that loss of inactivation of a tumor suppress gene in the supB- cells results in the observed structural changes and that the cell shape-dependent differences in growth and gene expression manifest by the supB- cells are directly related to these structural perturbations. The altered cell structure, anchorage-independent growth, and patterns of gene expression the correlate with loss of the tumor suppressor phenotype in these cells may be illustrative of a general mechanism relating cell shape, differentiation, and cancer.